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Basic Research On Bacteria: The Essential Frontier
Basic Research On Bacteria: The Essential Frontier
on Bacteria
The Essential Frontier
February 2007
1 the widespread perception that an adequate number of researchers in the U.S. in fields such as
bacterial physiology and genetics are not being trained,
2 the importance of basic knowledge of bacterial physiology and genetics in the biotechnology industry
and in applications including pathogenesis and biodefense,
3 the growing understanding of the impact of bacteria on human health, and on the development of chronic diseases.
To address these questions, the ASM and National Institutes of Health (NIH) jointly sponsored a workshop on Basic Research
in Bacteriology that was convened November 3-4, 2005 on the NIH campus in Bethesda, Maryland.
T
Approach Goal: The workshop
he ASM-NIH workshop focused on scientific gaps and participants focused on the
opportunities for research on bacteria. In order to stim-
ulate creative, goal-oriented interactions, the meeting inte-
following discussion areas:
grated focused discussions within smaller working groups • What are the gaps in our knowledge, methodologies,
and overarching sessions with entire group participation. and information access that must be addressed?
Participants in the two-day workshop included scientists What strategies would address these gaps?
with a variety of research expertise, representatives of
industry, and representatives of federal agencies. Following • How has microbiological research at the basic and
the meeting, the groupʼs Steering Committee prepared this applied levels been changed by technological advances
summary of the discussions and recommendations to (e.g., genomics, imaging, and computation)? What new
guide future research. opportunities have been revealed?
R
stand very little about the interactions between bacteria Evolving Priorities
and the environment that influence the delicate ecological
equilibrium between humans and microbes and thereby esearch on bacteria and their phages has led to many
determine the balance between health and disease. fundamental scientific discoveries. Initial support for this
research was justified in part because of the role of bacteria
In addition to the bacteria that are in or on the human body, in causing disease. With the advent of effective antibiotics it
bacteria influence humans in many other ways. Bacteria are seemed like the war on microbes had been won. Hence, for
the dominant occupant and architect of our entire biosphere. several decades health-related research shifted to topics
Bacteria sustain the metabolic cycles that are essential for all like cancer, heart disease, and genetic diseases. Moreover,
life on earth. Bacterial metabolism sculpts our physical envi- developments in molecular biology arising from research on
ronment as well. Because they are ubiquitous and have such bacteria made it possible to study many basic biological
diverse metabolic capabilities, bacteria influence essentially processes in mammalian cells, eliminating the argument
all disciplines of science, including fields such as evolutionary that bacterial model systems were the only doorway to
biology, ecology, immunology, cell and developmental biolo- eukaryotic molecular biology.
gy, psychology, geology, chemistry, physics, climatology,
computer science, and engineering. Meanwhile, the microbes demonstrated how rapidly they
could evolve new traits. Microbial resistance to antibiotics
Bacteria are also instrumental for understanding funda- developed faster than new antibiotics could be developed,
mental life processes that are required by all organisms, and the resistance spread throughout the microbial world.
including central metabolism, replication, transcription, The global expansion of food distribution networks facilitated
translation, protein targeting, assembly and structure the rapid distribution of microbial pathogens. Simultaneously,
of macromolecular complexes, protein folding, stress emerging microbial pathogens filled new ecological niches,
responses, error correction mechanisms, signal transduction, such as indwelling medical devices and the growing popula-
and developmental programs. These processes are more tion of humans who are immunocompromised due to pri-
easily characterized in model bacteria and their phages mary infections (including HIV) or due to therapies used to
than in other organisms because microbes provide such treat chronic diseases. Furthermore, recent discoveries
tractable experimental systems. The large repertoire of have demonstrated that some diseases (including ulcers,
genetic and biochemical tools and data that have been certain types of cancer, heart disease, etc.) that were pre-
acquired from basic research on bacteria is crucial for viously believed to be caused by a genetic predisposition
dissecting the complex metabolic and regulatory networks or exposure to environmental toxins are actually caused by
that control these processes. This provides a launching microbes. This microbial offensive has summoned a
point for understanding the enormous diversity in the
bacterial world and facilitates the understanding of these
processes in eukaryotes.
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renewed counter-attack on microbial pathogens.
Meanwhile, new tools have become available that make it
Impact of New Technologies
possible to dissect the molecular basis of pathogenesis ew approaches like genomics, transcriptomics, and
both from the microbial and host perspectives. Recently, proteomics allow the identification of the entire genetic
having the complete DNA sequences of bacterial complement of bacteria and which of these genes are turned
pathogens has provided valuable insights into how micro- on under particular conditions. Comparative genomics led to
bial pathogens evolve and the extent of gene transfer the discovery that gene exchange between bacteria is ram-
between pathogens. These advances have revealed new pant and has dramatically influenced the acquisition of viru-
ways to control infection, including the identification of lence, and had a major impact on our understanding of the
novel targets for antimicrobials and novel approaches for evolution of pathogenesis. However, interpretation of data
vaccine development. from these “omics” approaches relies on comparisons with
databases rather than direct functional assays. Thus, these
The value of basic research on bacteria has extended well
new approaches have not diminished the need for basic
beyond infectious diseases. Research on bacteria led to
research because a detailed understanding of microbial
the elucidation of important concepts of molecular biology,
physiology and genetics is essential to interpret and test the
allowing developments in biotechnology that have yielded
resulting predictions. In fact, the ability of “omics” approaches
tremendous benefits to many other aspects of human
to generate a tremendous number of predictions greatly
health and well-being as well as providing new tools that
increases the need for direct experimental tests based
have facilitated our understanding of pathogenesis. With
upon genetics, biochemistry, and molecular biology.
the advent of new tools that allowed us to extend beyond
Furthermore, the detailed characterization of the mecha-
pure culture studies to identify bacteria in complex commu-
nisms of discrete pathways and reactions, and molecular
nities in the environment, it became clear that bacteria
interactions that modulate these interactions is required for
have many roles in human health that were previously
understanding the integrated networks and for developing
unknown. These discoveries have opened important new
new ways to modulate these processes for our purposes—
opportunities for research on bacteria. Although these new
a major goal of systems biology.
technologies allow the rapid accumulation of data about
bacterial genes and gene expression, interpreting these Imaging is another technological advance that has provid-
data relies on many basic aspects of bacterial genetics, ed useful insights into bacterial physiology and pathogene-
physiology, and ecology that are not yet well understood. sis. Sensitive new approaches allow the visualization of
molecules within bacteria and bacteria within an infected
host. The applications of these approaches in bacterial
cell biology and ecology have only begun to be tapped.
Coupled with an understanding of bacterial physiology and
molecular biology, and the ability to genetically manipulate
these processes, will lead to new therapies that direct
active agents to particular sites in the host to combat
disease or stimulate health.
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• Antimicrobials—We desperately need innovative • Nanotechnology—To date most of our understanding of
approaches for the development of new classes of antibi- structure and function of bacteria comes from studies on
otics (vs. simply modifying existing classes of antibiotics). populations of cells. However, averaging data from a
Can we develop new methods to slow the development of large number of cells obscures important processes that
antibiotic resistance? Are the current regimes of antibiotic occur with single cells. Similar arguments can be made
therapy optimal? What does ecology tell us about predict- for single molecules. Understanding structure and func-
ing and managing antibiotic effectiveness? Answering tion at the single cell and single molecule level has
these questions will demand collaborations between important implications for nanotechnology. These ques-
microbiologists, chemists, and physicians. tions are enticing a new generation of physicists into
microbiology, but they are often hindered by inadequate
• Immunity and tolerance—The human immune system understanding of bacterial physiology and genetics.
is constantly interacting with the thousands of bacterial
species comprising our natural microbiota. Understanding • Bacterial physiology and genetics—Solving the problems
how the natural microbiota communicates with the immune described above demands a detailed understanding of
system and how the immune system singles out harmful basic molecular processes that mediate growth, metabo-
microorganisms could lead to the development of drugs lism, and regulation in microbial cells. Although commonly
that help the natural microbiota outcompete pathogens. described in textbooks as if they are completely understood,
there are many important, unresolved questions about
• Vaccines—We need new types of vaccines that provide basic bacterial genetics and physiology. For example,
effective protective immunity and can be used in young although when bacteria enter a host they must adapt to the
children and individuals with compromised immune sys- increased temperature and osmolarity, we do not know how
tems. Needs include more effective mechanisms of vac- genes are regulated in response to these physical changes.
cine delivery, vaccine targets that provide broad, long-
lasting immunity, and vaccine formulations that are stable In addition to insights on diseases, basic research on
outside a narrow window of temperature and humidity bacteria also leads to discoveries that benefit human
conditions. Development of these vaccines will require health in other ways, including the development of new
integration of the fields of immunology, bacterial genetics, tools for cloning and gene expression, the modulation of
comparative genomics, bioinformatics, and pathogenesis. metabolic pathways to overproduce useful end-products,
the use of microbes for nanotechnology, the use of microbes
• Detection and identification—Rapid diagnostic tools to for bioremediation of toxic waste and radioactivity, and the
allow identification of the disease-causing agent and its use of microbes for alternative energy production.
resistance profile would make it possible to reduce the
use of broad-spectrum antibiotics and encourage the Individual investigators with smaller lab groups provide the
development of targeted therapeutics that are less likely expertise needed to deal with the tremendous diversity of
to disrupt the natural microbiota. microbes, approaches, and scientific backgrounds required to
solve these varied problems. However, human resources will
• Chronic diseases—How do microbial infections stimulate need to be leveraged with shared access to sophisticated
chronic diseases? Once we understand how, can we equipment to carry out research at the increasingly complex
develop new therapies to intervene and thus prevent this levels now possible. In addition, major efforts will be needed
process? These questions extend to dental microbiology to capture, analyze, and share the prodigious streams of data
as well—for example, is there a relationship between peri- already resulting from modern technological approaches.
odontal disease and heart disease or premature births? Individual laboratories will need access to the most efficient
algorithms for such analyses, and access to tools that will
• Host-bacteria interactions—Genes that influence estab-
allow them to create their own knowledge environments.
lishment of microbial populations may influence the ability of
bacteria to cause disease. Identifying the host and bacterial
genes that influence colonization and virulence, and study-
ing the mechanics of the host-bacteria conversation, may
provide a novel approach for countering infections.
6
B
Summary
asic research on bacteria has had significant impact on
many areas of science. This research has revealed
many fundamental features of all living cells, and has
produced novel tools that allow us to study previously inac-
cessible problems. Discoveries continue to be made using
model systems such as Escherichia coli and many other
microbes with unique properties. Making discoveries often
relies upon insights from studying the physiology and
genetics of model organisms coupled with newly devel-
oped experimental tools and creative ideas.
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[available at http://www.nsf.gov/about/history/vbush1945.htm].
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Kaiser J. “Microbiology: Détente declared on NIH biodefense funding.” Science, 308:938 (2005).
Maloy S., Schaechter M. “The era of microbiology: a Golden Phoenix.” International Microbiology, 9: 1-7 (2006).
National Research Council. Treating Infectious Diseases in a Microbial World: Report of Two Workshops
on Novel Antimicrobial Therapeutics. National Academies Press, Washington, DC (2006).
Overbye K., Barrett J. “Antibiotics: where did we go wrong?” Drug Discovery Today, 10: 45-52 (2005).
Schaechter M., Kolter R., Buckley M. Microbiology in the 21st Century: Where Are We and Where Are We Going?
American Academy of Microbiology, Washington, DC (2003).
Schlegel H. “Continuing opportunities for general microbiology.” Archives of Microbiology, 182: 105-108 (2004).
Sleator R., Hill C. “Patho-biotechnology: using bad bugs to do good things.” Current Opinion in Biotechnology,
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In addition to the above discoveries that
emphasize the impact of microbiology prior
Appendix I Ecology and Evolution
• Extent of microbial diversity (>99% to the last decade, some recent examples
Some examples that demonstrate the
microbes uncultured; use of rRNA for of discoveries resulting from basic
impact of basic research on bacteria are
taxonomy) research on bacteria include the following.
listed below.
• Evolution of new traits (acquisition of
pathogenesis islands via horizontal gene
transfer)
Molecular Biology Development of New Antibiotics
• Cloning (plasmid and phage vectors;
and Inhibitors
• Coordination of microbial populations
restriction enzymes) • Use of genomics to identify antibiotic
(quorum sensing)
targets and vaccine candidates
• DNA sequencing • Growth of mixed microbial consortia as
• RNA and DNA aptamers as therapeutics
• PCR (Temperature stable polymerases) biofilms
(resulting from work on phage T4,
• Protein overexpression (phage T7; aptamer-based treatments are currently
chaperones) Medicine in clinical trials)
• Protein secretion • Discovery of antibiotics (streptomycin, • Quorum sensing via homoserine lactones
tetracyclines, vancomycin, bactricin, etc.) (required for virulence of some bacteria,
• Mutagenesis and DNA repair (discovered
inhibitors are being developed)
in bacteria; including mismatch repair • Antimetabolites (understanding of metabol-
which plays major role in certain cancers) ic pathways led to improved therapies, e.g. • Antibiotic resistance due to efflux pumps
trimethoprim plus sulfa) (new inhibitors in trials)
• Recombination (including site-specific
recombination systems used for genetic • Inhibitors of resistance mechanisms • Integrase inhibitors (studies on transposi-
engineering, and mechanisms of homolo- (e.g. ß-lactamase inhibitors such as tion mechanisms in bacteria leading to
gous recombination) clavulanic acid) the understanding of the mechanism of
HIV integrase, and the appreciation that
• Transposons (initial work in maize, but • Discovery of gyrase and other topoiso-
this enzyme is a good target for drug
molecular understanding from work in merases (led to quinolone antibiotics
development; novel peptide antibiotics
bacteria) such as ciprofloxacin, and anti-cancer
that inhibit recombination)
drugs such as etoposides that make
Type II topoisomerases toxic in rapidly • Antibiotic target interactions informing
dividing human cells) modification of existing antibiotics (ribo-
Metabolism and Biochemistry
• Role of proton motive force in transport, some structure allows development of
• Lipopolysaccharide structure (basis of
energy (substrate coupled proton fluxes new aminoglycosides; penicillin binding
septic shock)
in bacteria) proteins and mechanism of action of
• Function of eukaryotic genes (comparative penicillins; mechanism of resistance to
• LacY as paradigm for secondary trans- vancomycin; gyrase inhibitors, tRNA syn-
genomics of CFTR and P-glycoprotein
porters (many now implicated in disease) thase inhibitor Mupirocin)
sequences allowed prediction of their func-
• Regulation of gene expression (via a tion based upon similarity to bacterial ABC
• Determined sites of action for pesticides
diversity of mechanisms, including gene transporters)
(including Roundup and the sulfonylurea
rearrangements, transcription, translation, herbicides)
• Live, attenuated vaccines (e.g. Aro
turnover, etc.—most discovered by
mutants of Salmonella enterica sv. Typhi,
research in phage lambda and E. coli) • Role of biofilms in antibiotic resistance and
required understanding of physiology)
persistence (targets for novel antibiotics;
tissues, implants, etc.)
• Role of stress responses in antibiotic
persistence and development of cross-
resistance
• Phage therapy
• Streptokinase as inhibitors of thrombosis
subsequent to myocardial infarction
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Associate Professor, Department of
Laurie Comstock, Ph.D. Darren E. Higgins, Ph.D.
Appendix II
Channing Laboratory Microbiology and Molecular Genetics
Associate Professor of Medicine
Division of Microbiology and Infectious Diseases Rutgers University Professor and Chair, Microbiology
Samuel Kaplan, Ph.D.
San Diego State University Department of Pathobiology & Microbiology, Translational Genomics
University of Washington Research Institute (TGEN)
Northern Arizona University
CEO, Sequella, Inc.
Carol A. Nacy, Ph.D.
George Georgiou, Ph.D.
Professor, Center for Microbial Ecology Chemical Engineering, Biomedical Microbiology & Immunology
James M. Tiedje, Ph.D. Chair in Engineering #9
Michigan State University Engineering and Institute for Cell and University of Illinois-Chicago
Molecular Biology
University of Texas at Austin
Professor, Microbiology and
Roberto Kolter, Ph.D.
General Meeting Participants
Molecular Genetics
Harvard Medical School
William R. Goldman, Ph.D.
Frederick M. Ausubel, Ph.D.
Washington University School of Medicine
Professor of Molecular Microbiology
Department of Molecular Biology
Professor of Genetics
Harvard Medical School Professor and Director, Center for University of Wisconsin-Madison
Jeffrey Gordon, M.D.
Genome Sciences
Washington University
Research Fellow, Central Research &
Jonathan Beckwith, Ph.D. Robert A. LaRossa, Ph.D.
Stony Brook University Howard Hughes Medical Institute at the Michigan State University
Professor and Investigator
New York University School Professor, Department of Microbiology and University of Washington
G. Wesley Hatfield, Ph.D.
University of Washington
Professor of Medicine
University of Kansas Medical Center California Institute of Technology and Immunity Branch
National Institute of Child Health
and Human Development
Professor and Chair, Department of Professor and Chair, Department of National Institues of Health
Jeffery F. Miller, Ph.D. Magdalene So, Ph.D.
Professor, Department of Cell Biology and Metabolism Branch and Infectious Diseases
Charles P. Moran, Jr., Ph.D. Senior Investigator
Microbiology & Immunology National Institute of Child Health National Institutes of Health
Emory University School of Medicine and Human Development
National Institutes of Health Ann Lichens-Park, Ph.D.
Professor, Biochemistry/
Kit Pogliano, Ph.D. Ryland Young, Ph.D. Program Officer Bacteriology
University of California, San Diego Texas A&M University and Infectious Diseases
National Institutes of Health
Wyeth
Federal Meeting Participants N. Kent Peters, Ph.D.
Program Officer Bacteriology
Developmental Biology
Keck Graduate Institute National Institutes of General Medical
Molly Schmid, Ph.D.
Princeton University
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Starting with bottom row, left to right:
Row 1: Linda J. Kenney, William R. Jacobs,
Jr., Michael Schaefer, Magdalene So,
Barbara Mulach